Metastasis is the major cause of morbidity and mortality in cancer. Approximately 30-40% of all diagnosed breast cancers eventually develop lesions in lymph nodes, lung, liver and bone. The stromal-derived factor SDF-1 (or CXCL12) is secreted by stroma in potential metastatic sites and attracts circulating chemokine receptor 4 (CXCR4) expressing cells. CXCR4 is often overexpressed in breast cancer cells and CXCR4- CXCL12 signaling is central not only for the migration of cancer cells but also for the survival and growth of micrometastatic and primary tumors. Inhibitors targeting CXCR4 reduce the incidence of metastasis. Of the known molecular phenotypes, triple negative (TN) [estrogen receptor (ER), progestin receptor (PR) and HER-2 negative] breast cancer patients have the worst prognosis, with most patients likely to experience distant recurrence and refractory disease. Nearly 75% of TN breast cancers have high levels of activated CXCR4 and this overexpression in TN breast cancers results in poor clinical outcome. Because of its critical role in cancer cell survival, invasion, recruitment of myeloid bone marrow-derived cells and angiogenesis, noninvasive imaging of CXCR4 receptor in TN breast cancer is important to evaluate elevated CXCR4 expression in primary and metastatic tumors. CXCR4 based imaging probes can be used i) to evaluate primary tumors for elevated CXCR4 expression and therapeutic intervention; ii) to screen for secondary metastatic spread to both local and distant sites; and, iii) for therapeutic monitoring. We previously developed and evaluated the positron emission tomography (PET) imaging agent [64Cu]AMD3100 in orthotopic and experimental lung metastatic models of breast cancer to detect CXCR4 expression. More recently, we developed the positron-emitting monocyclam analog [64Cu]AMD3465, which has nearly 16-fold higher binding affinity to CXCR4 when compared to [64Cu]AMD3100, and has provided the clearest images with very high target selectivity. Our purpose here is to develop an 18F-labeled AMD3465 analog for rapid clinical translational imaging of breast cancer. Also, TN breast cancers particularly lack the benefit of targeted therapy and show higher recurrence rates and shorter survival than other phenotypes. Targeting and selective depletion of lethal CXCR4 positive cancer cell populations within the tumors and metastases would likely to result in reduced metastatic burden. Because CXCR4 is highly expressed in TN breast cancers, we will develop therapeutic agents decorated with clinically available CXCR4 binding motifs and multimodality imaging reporters for targeting CXCR4 positive TN breast cancers. Relevance CXCR4 based imaging probes and CXCR4 targeted therapeutic agents that selectively eliminate CXCR4 positive cells within the primary tumors and metastases will be developed for imaging and targeting of triple negative breast cancer. PUBLIC HEALTH RELEVANCE: Metastasis is the major cause of mortality and triple negative (TN) breast cancers has the worst prognosis and survival. Chemokine Receptor 4(CXCR4) is expressed in majority of TN breast cancers. With an ultimate goal of clinical translation, we intend to synthesize CXCR4 binding PET imaging and therapeutic agents for identifying and targeting metastatic disease, respectively.